本文關(guān)鍵詞： 慢性鼻-鼻竇炎 骨膜蛋白 炎癥 重塑　出處：《山東大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：研究背景和目的:依據(jù)EPOS2012,鼻-鼻竇炎被定義為:鼻腔和鼻竇的炎癥,具有兩個(gè)或兩個(gè)以上的癥狀特征,其中一個(gè)必備條件是鼻塞/鼻堵,或鼻漏(前后鼻孔滴漏),可以伴或不伴面部疼痛/壓迫感、嗅覺減退或喪失;并且鼻內(nèi)鏡檢查所見:鼻腔息肉,并且/或伴有主要來(lái)源于中鼻道的黏膿性分泌物,并且/或伴有主要位于中鼻道的黏膜水腫或阻塞;或CT檢查:伴有竇口鼻道復(fù)合體和/或鼻竇的黏膜改變1。慢性鼻-鼻竇炎的癥狀持續(xù)時(shí)間不少于12周,并且癥狀未徹底消失。在臨床上,可將慢性鼻-鼻竇炎(CRS)分為慢性鼻-鼻竇炎伴鼻息肉(CRSwNP)和慢性鼻-鼻竇炎不伴鼻息肉(CRSsNP),對(duì)于慢性鼻-鼻竇炎伴鼻息肉,有學(xué)者依據(jù)鼻息肉中浸潤(rùn)細(xì)胞的種類和數(shù)量,把慢性鼻-鼻竇炎伴鼻息肉分為嗜酸性粒細(xì)胞型、中性粒細(xì)胞型、非嗜酸性粒細(xì)胞非中性粒細(xì)胞型2。不同的慢性鼻-鼻竇炎表型,其各自的內(nèi)在病理生理學(xué)特點(diǎn)存在差異,這種差異可能預(yù)示不同的發(fā)病機(jī)制,識(shí)別不同的發(fā)病機(jī)制可通過(guò)特定的生物標(biāo)志物來(lái)完成,已經(jīng)發(fā)現(xiàn)某些生物學(xué)標(biāo)志物,如血液中特異性IgE、金黃色葡萄球菌內(nèi)毒素IgE等,可作為慢性鼻-鼻竇炎的不同內(nèi)在型的生物標(biāo)志物3,并且針對(duì)不同內(nèi)在型的標(biāo)志物可以選擇個(gè)體化的治療4,5。研究報(bào)道骨膜蛋白(Periostin)是嗜酸性粒細(xì)胞性哮喘患者呼吸道炎癥的全身性生物標(biāo)志物6,7,參與哮喘患者呼吸道黏膜上皮下組織纖維化等結(jié)構(gòu)重塑8,9。上下呼吸道常常同時(shí)存在炎癥10,組織病理學(xué)研究發(fā)現(xiàn)與哮喘患者下呼吸道結(jié)構(gòu)重塑相一致,在慢性鼻-鼻竇炎患者鼻腔鼻竇組織中也存在結(jié)構(gòu)重塑11。由此我們推測(cè),在慢性鼻-鼻竇炎的組織中,可能存在骨膜蛋白的表達(dá),這種表達(dá)在不同的慢性鼻-鼻竇炎表型可能具有差異,這種差異對(duì)于認(rèn)識(shí)慢性鼻-鼻竇炎的內(nèi)在分型具有重要意義,與慢性鼻-鼻竇炎的發(fā)病機(jī)制有一定的關(guān)系。在哮喘患者中,血清中升高的骨膜蛋白與一種特殊的哮喘表型-嗜酸性粒細(xì)胞型哮喘有一定關(guān)系,并且經(jīng)常合并有阻塞性肺功能障礙和鼻部疾病12,在Th2型(IL-5、IL-13高表達(dá))、伴有較高的嗜酸性粒細(xì)胞的哮喘表型中,與血中嗜酸性粒細(xì)胞數(shù)、痰中嗜酸性粒細(xì)胞相比,血清中骨膜蛋白對(duì)于檢測(cè)氣流受限具有更高的敏感性13,血清中骨膜蛋白可以作為哮喘的生物標(biāo)志物,主要表現(xiàn)在兩個(gè)方面:一是作為Ⅱ型免疫反應(yīng)的生物標(biāo)志物代替指標(biāo),二是作為反映14組織重塑或纖維化的生物標(biāo)志物14。已有研究發(fā)現(xiàn)在慢性鼻-鼻竇炎伴鼻息肉中,59. 6%存在嗜酸性粒細(xì)胞(EOS)浸潤(rùn),嗜酸性粒細(xì)胞浸潤(rùn)在慢性鼻-鼻竇炎(CRS)15的病理生理過(guò)程中處于中心位置15。在嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉中,骨膜蛋白的表達(dá)可能與嗜酸性粒細(xì)胞的浸潤(rùn)有一定的關(guān)系,進(jìn)而可能與嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉的形成有關(guān)。目的:我們的研究旨在觀察骨膜蛋白在慢性鼻-鼻竇炎不同表型的表達(dá),分析其在慢性鼻-鼻竇炎病理生理過(guò)程中的作用,為慢性鼻-鼻竇炎的內(nèi)在分型提供可能的依據(jù)。方法:選擇住院患者,分為慢性鼻-鼻竇炎不伴鼻息肉組(CRSsNP、19例)、慢性鼻-鼻竇炎伴鼻息肉組(CRSwNP、36例)、鼻中隔偏曲組(DNS、15例)。分別留取慢性鼻-鼻竇炎不伴鼻息肉組的篩竇黏膜和慢性鼻-鼻竇炎伴鼻息肉組患者的篩竇黏膜組織與鼻息肉組織、鼻中隔偏曲患者的下鼻甲組織作為標(biāo)本,對(duì)慢性鼻-鼻竇炎伴鼻息肉組標(biāo)本進(jìn)行HE染色,依據(jù)嗜酸性粒細(xì)胞的浸潤(rùn)情況,將慢性鼻-鼻竇炎伴鼻息肉組分為嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組(ECRSwNP)和非嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組(NonECRSwNP),對(duì)四組標(biāo)本進(jìn)行骨膜蛋白免疫組織化學(xué)染色(IHC)、實(shí)時(shí)定量逆轉(zhuǎn)錄-聚合酶鏈?zhǔn)椒磻?yīng)(RT-PCR),觀察骨膜蛋白分子及mRNA在四組標(biāo)本的表達(dá);通過(guò)酶聯(lián)免疫吸附試驗(yàn)(ELISA)法檢測(cè)四組患者血清中骨膜蛋白的濃度。并對(duì)局部組織中免疫組織化學(xué)染色評(píng)分、骨膜蛋白mRNA、嗜酸性粒細(xì)胞浸潤(rùn)和血清中骨膜蛋白濃度、血液中嗜酸性粒細(xì)胞比例分別進(jìn)行各指標(biāo)間相關(guān)性分析。結(jié)果:骨膜蛋白免疫組化染色顯示,骨膜蛋白在四組標(biāo)本中的表達(dá)主要位于鼻黏膜上皮的基底膜、上皮下的纖維組織。慢性鼻-鼻竇炎不伴鼻息肉組(篩竇黏膜)、嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組(篩竇黏膜、鼻息肉)、非嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組(篩竇黏膜、鼻息肉)和鼻中隔偏曲組(下鼻甲黏膜)的免疫組化染色評(píng)分分別為3.19±0.98、3. 90±0. 42/4.17士0.52、3.20±0.86/3.32±0.84和2.44±0.86,慢性鼻-鼻竇炎不伴鼻息肉組、嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組以及非嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組評(píng)分高于鼻中隔偏曲組,差異具有統(tǒng)計(jì)學(xué)意義(P0. 05、P0.01、P0. 01)。嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組高于其他三組,差異具有統(tǒng)計(jì)學(xué)意義(P0. 01)。慢性鼻-鼻竇炎不伴鼻息肉組、非嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組之間相比較,差異無(wú)統(tǒng)計(jì)學(xué)意義(P0. 05)。通過(guò)酶聯(lián)免疫吸附方法測(cè)得四組患者血清中的骨膜蛋白濃度,慢性鼻-鼻竇炎不伴鼻息肉組、嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組、非嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組和鼻中隔偏曲組血清中骨膜蛋白濃度分別為47962. 77±14307. 30、72138. 91 ± 21722.43、43012.45 ± 10314. 95 和 31337.81 士8181. 02pg/ml。嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組明顯高于其他三組,差異具有統(tǒng)計(jì)學(xué)意義(P0. 01),鼻中隔偏曲組低于其他三組,差異具有統(tǒng)計(jì)學(xué)意義(P0. 01),慢性鼻-鼻竇炎不伴鼻息肉組與非嗜酸性慢性鼻-鼻竇炎伴鼻息肉組相比無(wú)明顯差異(P0. 05)。四組患者鼻黏膜組織中均有骨膜蛋白mRNA,慢性鼻-鼻竇炎不伴鼻息肉組、嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組、非嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組和鼻中隔偏曲組鼻黏膜組織骨膜蛋白mRNA分別為 0.351156 ±0.250896、0.477044 ±0.505552、0.326074 ±0.412194和0.340352±0. 304540,與鼻中隔偏曲組相比,慢性鼻-鼻竇炎不伴鼻息肉組、嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組、非嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組鼻黏膜組織中骨膜蛋白mRNA升高,但差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)。在嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉組,鼻息肉組織中骨膜蛋白分子的表達(dá)與局部組織(篩竇黏膜、鼻息肉)中嗜酸性粒細(xì)胞的浸潤(rùn)具有一定相關(guān)性(P0. 01,P0. 05),血清骨膜蛋白濃度與血中嗜酸性粒細(xì)胞比例具有一定的相關(guān)性(P0. 01)。在四組標(biāo)本中,局部組織中骨膜蛋白分子的表達(dá)與血中嗜酸性粒細(xì)胞比例無(wú)明顯相關(guān)性(P0. 05)。篩竇黏膜骨膜蛋白mRNA的表達(dá)與局部組織中嗜酸性粒細(xì)胞浸潤(rùn)、血中嗜酸性粒細(xì)胞比例無(wú)明顯相關(guān)性(P0. 05)。結(jié)論:1、骨膜蛋白作為炎性介質(zhì)之一,參與慢性鼻-鼻竇炎的慢性炎癥過(guò)程。2、骨膜蛋白參與嗜酸性粒細(xì)胞性慢性鼻-鼻竇炎伴鼻息肉的發(fā)病過(guò)程,這與嗜酸性粒細(xì)胞的浸潤(rùn)具有一定的正相關(guān);3、骨膜蛋白參與慢性鼻-鼻竇炎不同分型的組織重塑過(guò)程。
[Abstract]:Background and objective: Based on the EPOS2012, rhinosinusitis is defined as inflammation of the nasal cavity and paranasal sinus, with two or more than two of the symptoms, which is a necessary condition for nasal / nasal obstruction, rhinorrhea (or nasal drip), with or without facial pain / oppression, loss or loss of smell; and endoscopic findings: nasal polyps, and / or with mainly from the nose of the sticky purulent secretions, and / or with mainly located in the middle meatus mucosa edema or obstruction; or CT examination: with the ostiomeatal complex and / or sinus mucosa of 1. chronic rhinitis sinusitis symptoms duration of not less than 12 weeks, and the symptoms did not disappear. In clinic, the chronic rhinosinusitis (CRS) for chronic sinusitis with nasal polyps (CRSwNP) and chronic nasal sinusitis without nasal polyps (CRSsNP), for chronic rhinosinusitis with the nasal According to different types of polyps, some scholars and the number of cell infiltration in nasal polyps, the chronic sinusitis with nasal polyps were divided into eosinophils, neutrophils, non eosinophilic non neutrophil type 2. different phenotypes of chronic rhinosinusitis, their intrinsic pathophysiological characteristics the difference, this difference may indicate different etiology, pathogenesis can identify different specific biomarkers to complete, have found some biological markers, such as specific IgE in the blood, Staphylococcus aureus endotoxin IgE, can be used as different internal chronic rhinosinusitis biomarkers of 3. And you can select the individualized treatment of 4,5. research reports for internal Periostin symbol of different types of animals (Periostin) is eosinophilic airway inflammation in patients with asthma and systemic biomarkers 6,7, In patients with respiratory tract mucosa on asthma subcutaneous tissue fibrosis and other structural remodeling of 8,9. lower respiratory tract inflammation in 10 often exist at the same time, research findings were consistent with the respiratory tract of patients with asthma under tissue remodeling pathology in patients with chronic rhinosinusitis nasal tissues also exist in the remodeling of 11. we conclude that in patients with chronic rhinosinusitis group in the expression of Periostin may exist, this expression in chronic nasal sinusitis may have different phenotypic differences, this difference has important significance for understanding the intrinsic type of chronic nose - sinusitis, have a certain relationship with the pathogenesis of chronic rhinosinusitis. In patients with asthma and elevated serum Periostin with a special asthma phenotype - eosinophilic asthma have a certain relationship, and often associated with obstructive pulmonary dysfunction and nasal disease in 12, Th2 Type (IL-5, high expression of IL-13), with a higher eosinophilic asthma phenotype, the number of eosinophils in blood and sputum eosinophils, compared with periosteum proteins in serum for detection of airflow limitation has a higher sensitivity of 13, periosteal proteins in serum can be used as biomarkers for asthma that is mainly manifested in two aspects: one is the type of immune response biomarkers instead of two indicators, as reflected in 14 tissue remodeling or fibrosis biomarkers of 14. have been found in chronic sinusitis with nasal polyps, 59.6% eosinophilic infiltration of eosinophil infiltration (EOS), acid particle cells in patients with chronic rhinosinusitis (CRS) 15 pathophysiological processes in the center position of 15. in eosinophilic chronic rhinosinusitis with the nasal polyps, the expression of Periostin may be and eosinophil infiltration The relationship between, and may be related to the formation of eosinophilic chronic rhinosinusitis with the nasal polyp. Objective: our study aimed to investigate the expression of Periostin in chronic rhinosinusitis with different phenotypes, in the analysis of the pathophysiology of chronic rhinosinusitis, may provide a basis for the internal classification of chronic rhinitis sinusitis. Methods: inpatients were divided into chronic sinusitis without nasal polyps (19 CRSsNP cases), chronic sinusitis with nasal polyps (group CRSwNP, 36 cases), nasal septum group (DNS, n = 15). The organization of ethmoid mucosa tissue and nasal polyps were collected chronic sinusitis without nasal polyps group and ethmoid sinus mucosa of chronic sinusitis with nasal polyps patients, patients with nasal septum deviation in inferior turbinate tissues as specimens of chronic rhinosinusitis with the nasal polyp group specimens were stained with HE, on the basis of eosinophil The infiltration, the chronic sinusitis with nasal polyps were divided into eosinophilic chronic rhinosinusitis with the nasal polyp group (ECRSwNP) and non eosinophilic chronic rhinosinusitis with the nasal polyp group (NonECRSwNP), immune tissue of the four groups were Periostin staining (IHC) and real-time quantitative reverse transcription polymerase chain reaction (RT-PCR), to observe the expression of Periostin protein molecules and mRNA in the four groups; by enzyme-linked immunosorbent assay (ELISA) method to detect the concentration of serum protein was four. And the local tissue free immunohistochemical staining scores, Periostin Periostin mRNA, eosinophil the concentration of eosinophil infiltration and the serum, blood eosinophil percentage were analyzed the correlation between indexes. Results: Periostin immunohistochemical staining showed that the expression of Periostin in four groups were mainly located in the nose The basement membrane of the epithelium, subepithelial fibrous tissue. Chronic sinusitis without nasal polyps (ethmoid mucosa), eosinophilic chronic rhinosinusitis with the nasal polyp group (ethmoid mucosa, nasal polyps), non eosinophilic chronic rhinosinusitis with the nasal polyp group (ethmoid mucosa), nasal polyps and nasal septum deviation group (inferior turbinate) immunohistochemical staining scores were 3.19 + 90 0.98,3. + 0. 42/4.17 + 0.52,3.20 + 0.86/3.32 + 0.84 and 2.44 + 0.86, chronic sinusitis without nasal polyps, eosinophilic chronic rhinosinusitis with the nasal polyp group and non eosinophilic chronic rhinosinusitis with the nasal polyp group was higher than that of nasal septum group, the difference was statistically significant (P0. 05, P0.01 01, P0.). Eosinophilic chronic rhinosinusitis with the nasal polyp group than the other three groups, the difference was statistically significant (P 0.01). Chronic sinusitis without nasal polyps, non eosinophilic chronic sinusitis with nasal polyps between group comparison, no statistically significant difference (P0.. 05) by ELISA method to measure the concentration of Periostin four groups in the serum of patients with chronic rhinosinusitis without. Nasal polyps, eosinophilic chronic rhinosinusitis with the nasal polyp group, non eosinophilic chronic sinusitis with nasal polyps and nasal septum deviation group Periostin protein concentrations were 47962.77 + 14307. and 3072138.91 + 21722.4343012.45 + 10314.95 and 31337.81 + 8181. 02pg/ml. eosinophilic chronic rhinosinusitis with nasal polyps group was significantly higher than that of the other three groups in the serum, the difference was statistically significant (P0. 01), nasal septum group was lower than that of the other three groups, the difference was statistically significant (P0. 01), chronic nose sinusitis without The nasal polyp group and non eosinophilic chronic rhinosinusitis with the nasal polyp group showed no significant difference (P0. 05). Four groups of patients had periosteal protein mRNA in nasal mucosa, chronic nasal sinusitis without nasal polyps, eosinophilic chronic rhinosinusitis with the nasal polyp group, non eosinophilic cell chronic rhinosinusitis with periosteal protein mRNA in nasal polyps and nasal septum nasal mucosa tissue were 0.351156 + 0.250896,0.477044 + 0.505552,0.326074 + 0.412194 and 0.340352 + 0.304540, compared with the deviation of nasal septum, chronic nasal sinusitis without nasal polypus group, eosinophilic chronic rhinosinusitis with nasal polyps group, non eosinophilic chronic rhinosinusitis with periosteal protein mRNA in nasal polyps in the nasal mucosa increased, but the difference was not statistically significant (P0.05). In eosinophilic chronic rhinosinusitis with breath Meat group, expression of Periostin protein molecules in nasal polyps and local tissue (ethmoid mucosa, nasal polyps) is a relationship between the infiltration of eosinophils in the eosinophil (P0. 01, P0. 05), serum Periostin concentration and blood eosinophil proportion has certain correlation (P0. 01) in the four groups. The expression of blood specimens, and periosteal protein molecules in the local tissue eosinophil ratio had no significant correlation (P0. 05). The expression of mRNA protein and the periosteum of ethmoid mucosa tissue eosinophil infiltration, blood eosinophil percentage had no significant correlation (P0. 05). Conclusion: 1, periosteal protein is one of the inflammatory mediators,.2 chronic inflammatory process in chronic rhinosinusitis, Periostin protein involved in the pathogenesis of eosinophilic chronic rhinosinusitis with the nasal polyps, and the infiltration of eosinophils has certain positive correlation; 3, Periosteum protein participates in the process of tissue remodeling in different types of chronic rhinosinusitis.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R765

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本文編號(hào)：1442009